Hydroxyaryl-alkyl and aralkyl sulphides



Patented Mar. 23, I937 PATENT OFFICE HYDROXYARYL-ALKYL AND ARALKYL SULPHIDES 9 Ellis Miller, Philadelphia, Pa., assignor to Sharp & Dohme, Inc., Philadelphia, Pa., a corporation of Maryland No Drawing. Application September 25, 1933,

Serial N0. 690,944

12 Claims.

This invention relates to new hydroxyaryl alkyl and aralkyl sulphides and methods of preparing hydroxyaryl-alkyl and -ara1kyl sulphides. It includes hydroxyphenyl-alkyl sulphideswhlch have three or four or more carbon atoms in the side chain and which have a high phenol coeificient and valuable therapeutic properties. It also includes the hydroxyaryl-aralkyl sulphides. The invention relates particularly to the hydroxypheny1-butyl -amyl and -hexyl sulphides and the hydroxyphenyl-aralkyl sulphides.

In the following table certain of these compounds arelisted together with their chemical properties. It will be observed that the higher hydroxyphenyl-alkyl sulphides, viz., those having three, four, five and six carbon atoms in the side chain have a. higher phenol coefficient than those members of the series which have but one or two carbon atoms in the side chain.

sulphide. An aralkyl halide may be employed to form an aralkyl sulphide. In the second method an ether of an aryl diazonium compound is coupled with an alkyl or aralkyl mercaptan, the diazo compound is heated to remove the nitrogen and unite the sulphur directly with the aryl group, and thecompound then de-etherified. The compounds prepared by either method may be purified for 'medicinal use by recrystallization from organic solvents. The two methods will be exemplified by detailed descriptions of thepreparation of para-hydroxyphenyl n-butyl sulphide.

Example '1 parts of sodium hydroxide are partially dissolved in 50 parts of methyl alcohol. To this is added a solution of 58.3 parts of thiohydroquinone, C6H4(OH) (SH), in 50 parts of methyl alcohol. The mixture is stirred and then 68 parts Phenol Melting coefii- Boiling point, 0. point,

cient 0.

1 HO-OuH4-SCH3 P-hydroxyphenyl-methyl sulphide.. 8 113 (6 mm.)

2 HOCuHi-SCH2OH3 P-hydroxyphenyl-ethy1sulphide.-- 10 1535 (13 mm.) 41 3 HOCnH4SCH2OH2CHa P-hydroxyphenyl-n-propyl sulphide. 36 1503 (5-6 mm.) 37 4 HOCaHr-SCH2CHzCH2GHs P-hydroxyphenyl-n-butyl sulphide 77 1668 (7 mm.) 49-50 5 HO-C0H4SCH2CHzOHzCHzCHa 120 {175-80" (8-10 mm.)

P-hydroxyphenyl-n-amyl sulphide. idl -68 (3-4 mm.) 6 HO-C&H4SCHzCHzCHgCHgCHzCHa {194-96 (16 mm.) 600 P-hydroxyphenyl-n-hexyl sulphide.- 17880 (5 mm.); 7 HO-C0H4SCH(GH3)2 P-hydroxyphenyl-isopropyl sulphide. 20 1502 (13 mm.) 8 HO-CoH4-SCH2CH(CH3)2 P-hydroxyphenyl-isobutyl sulphide- 61 159-62" (10 mm.) 9 nooum-somonioe om)z P-hydroxyphenyl-isoamyl sulphide. 30 1502 (3 mm.)...; .10 HOCoH4-SOHzCtHs P-hydroxyphenyl-benzy1 sulphide... 2205 (15 mm.).... 104 11 HO-CeH4-SCH2CH2CH2CHa M-hydroxyphenyl-butyl sulphide 127-140" (4 mm)...

40 The -isopropyl and -isobuty1 sulphides are liquid.

The phenol coefficient of p-hydroxyphenyl-nhexyl sulphide and p-hydroxyphenyl-benzyl sulphide measured by the usual. procedure was 0, i. e., a saturated solution was inert. When these products were dissolved 111000 in N/100 sodium hydroxide and further dilutions made with water, the values 230 and 20 were obtained. The so1ubility of the p-hydroxy-phenyl-n-hexyl sulphide is apparently less than 1:10,000 in water.

There are two methods of preparing these compounds in sufficiently pure form for medicinal use. In the first method thiohydroquinone or other hydroxythiophenol is caused to react with 55 an alkyl halide to form the hydroxyaryl alkyl of n-butyl bromide are added during the course of fifteen-minutes. Reaction sets in at once and proceeds vigorously with the evolution of heat and the formation of a voluminous precipitate of sodium-bromide. The resulting'mass is refluxed for about an hour. It is allowed to cool and is then filtered. The filtrate is distilled to remove methyl alcohol which is recovered and may be reused. The residual oil is then washed with water and it may be extracted with benzene and distilled in vacuo. The major fraction of the para-hydroxyphenyl-butyl sulphide which distills over boils at 165-8 C. (7 mm). It solidifies on standing to a white crystalline mass which when recrystallized from benzene-ligroin mixture melts at 49-50 C.

By using other alkyl halides, e. g., propyl, amyl, hexyl, isopropyl, isobutyl, isoamyl or isohexyl bromide or aralkyl halides, e. g., benzyl, phenylethyl, tolylethyl or naphthylmethyl bromide instead of the n-butyl bromide of this example, the corresponding para compounds may be prepared. Starting with m-CsH4(OI-I) (SH), meta alkyl and aralkyl compounds may be prepared. By starting with a substituted thio monohydroxy phenol, for example, the tolyl derivative, other hydroxy arylalkyl or aralkyl sulphides are obtained.

Example 2 68.5 parts of para-phenetedine,

NH2CeH4-OC2H5 are dissolved in an excess of 10 per cent hydrochloric acid. This solution is cooled below 15 C. and diazotized by the gradual addition of 35 parts of sodium nitrite in aqueous solution while the temperature is maintained at 15-20 C. by means of ice.

The diazo solution is then run slowly beneath the surface of a hot solution of 49.5 parts of n-butyl-mercaptan C4H9-SH, in 400 parts of 20% caustic soda, care being taken to stir the mixture vigorously and maintain the temperature at -75" C. When all the diazo solution is in, the temperature is raised to C. and this is maintained until no further evolution of nitrogen is observed. The solution is then allowed to cool down to room temperature and is acidified with concentrated hydrochloric acid. A heavy black oil separates. The oil is washed first with dilute hydrochloric acid and then with water and is distilled in vacuo yielding an intermediate product, viz., paraethoxyphenyl butyl sulphide with a boiling point of about 160 C. (12 mm.) This ether is then de-ethylated by refluxing at 75-85 C. for a number of hours with an excess of 20% hydrobromic acid in glacial acetic acid. When the de-ethylation is practically complete the excess hydrobromic-acetic acid mixture is removed by vacuum distillation. Ester present in the residual oil is then hydrolized by refluxing with 10 per cent caustic soda dissolved in 25% alcohol. The alcohol is then distilled off leaving in solution the sodium salt of para-hydroxyphenyl-n-butyl sulphide. This solution is extracted a number of times with benzene to remove any un-de-ethylated product and the water solution is acidified with hydrochloric acid. The oil which separates is taken up with benzene, washed with water and distilled in vacuo. A white crystalline product melting at 48 C. is obtained. Recrystallized from benzene-ligroin mixture, it melts at 49-50 C.

Other alkyl mercaptans may be employed instead of n-butyl mercaptan to prepare other para compounds, e. g., normal and isopropyl, amyl and hexyl mercaptans and isobutyl mercaptans. Aralkyl compounds may be made by using aralkyl mercaptans such as normal phenyl and naphthyl methyl and ethyl, etc. mercaptans. Starting with meta NH2-C6H4OC2H5 or other ether, meta hydroxyaryl-alkyl or -aralkyl sulphides may be prepared. By starting with a substituted amino aryl ether, such as an amino tolyl other other hydroXyaryl-alkyl and aralkyl sulphides are obtained.

The new compounds of this invention are valuable as antiseptics and have a relatively high phenol coeflicient as compared with para hydroxyphenyl-ethyl sulphide.

I claim:

1. Antiseptics having the formula where one X stands for OH and the other stands for hydrogen and R is a member of the group consisting of aralkyl radicals and alkyl radicals containing three or more carbon atoms.

2. Para-hydroxyphenyl-alkyl sulphides having at least three carbon atoms in the alkyl group and having a high phenol coeflicient.

. Para-hydroxyphenyl-butyl sulphides.

. Para-hydroxyphenyl-amyl sulphides.

. Parahydroxyphenyl-hexyl sulphides.

. Para-hydroxyphenyl-n-butyl sulphide.

. Para-hydroxyphenyl-n-amyl sulphide.

. Para-hydroxyphenyl-n-hexyl sulphide.

The method of preparing compounds of the group consisting of hydroxy aryl -alkyl and -aralkyl sulphides which comprises reacting in the presence of an alkali an halide from the group consisting of alkyl and aralkyl halides with a compound having the formula HOP.,-SH where R is an aryl group.

10, The method of preparing para-hydroxyphenyl-alkyl sulphides which comprises reacting thiohydroquinone with an alkyl bromide in the presence of an alkali.

11. The method of preparing para-hydroxyphenyl-alkyl sulphides which comprises dissolving sodium hydroxide and thiohydroquinone in a solvent, gradually adding an alkyl bromide thereto, maintaining the temperature at the refluxing point at least until the reaction nears completion, filtering off the sodium bromide which has been precipitated and then recovering para-hydroxyphenyl-alkyl sulphide from the residue.

12. The method of preparing para-hydroxyphenyl-n-butyl sulphide which comprises dissolving sodium hydroxide and slightly more than an equivalent amount of thio-hydroquinone in a suitable organic solvent, adding n-butyl bromide to the solution, the sodium hydroxide and the bromide being used in equimolecular proportions and the bromide being stirred into the solution gradually While reaction sets in which forms a voluminous precipitate of sodium bromide, the mass being kept hot until the preparation of the para-hydroxyphenyl-butyl sulphide has reached substantial completion, then filtering oif sodium bromide which has been formed, extracting the remaining filtrate, and distilling para-hydroxyphenyl-n-butyl sulphide from the extract.

ELLIS MILLER. 

